Obesity is a chronic disease manifested by an excess of fat mass in proportion to body size. Today, every third American is considered overweight (Body Mass Index (BMI)>25 kg/m2). Obesity predisposes to Type 2 Diabetes, congestive heart failure, osteoarthritis, sleep apnea, Metabolic Syndrome, atherogenic dyslipidemia, elevated blood pressure and insulin resistance. Even a modest decrease in body weight (5-10% of initial body weight) may significantly lower the risk factors for developing obesity-associated diseases (Wing et al., Arch. Intern. Med. 147:1749-53 (1987); Tuomilehto et al., New Engl. J. Med. 344:1343-50 (2001); Knowler et al., New Engl. J. Med. 346:393-403 (2002); Franz et al., Diabetes Care 25:148-98 (2002)). Additionally, treatment of obesity may be important from a mental health perspective due to the social stigma often attached to obese individuals in some cultures.
The melanocortin system plays a major role in the regulation of energy balance and food intake (Garfield et al., Trends Endocrinol Metab. 20:203-15 (2009)). In humans and rodents, loss of function mutations in the different components of the melanocortin system are closely correlated with obesity and related conditions. In mice, mutations within the melanocortin receptor 4 (MC4R), melanocortin receptor 3 (MC3R) or pro-opiomelanocortin (POMC) produce obesity, insulin resistance and hyperphagia (Goodfellow and Saunders, Curr. Topics Med. Chem. 3:855-83 (2003); Huszar et al., Cell 88:131-41 (1997); Yaswen et al., Nat. Med. 5:1066-70 (1999)). In man, mutations within POMC or MC4R lead to the development of obesity associated with increased food intake (Krude et al., Nat. Genet. 19:155-7 (1998); Yeo et al., Nature Genetics 20:111-2 (1998); Branson et al., New Engl. J. Med. 348:1096-103 (2003); Vaisse et al., J. Clin. Invest. 106:253-62 (2000); Ho and MacKenzie, J. Biol. Chem. 275:35816-22 (1999)). Pharmacological stimulation of MC4R leads to decreased food intake, increased energy expenditure and weight loss in rodents (Pierroz et al., Diabetes 51:1337-45 (2002)). In man, the intranasal administration of MC4R agonist alpha-MSH results in decreased body weight due to the decreased fat mass (Fehm et al., J. Clin. Endo. Metabol. 86:1144-48 (2001)). The wild type alpha-MSH is of limited use as a pharmaceutical due to its extremely short serum half-life. Alpha-MSH analogs have been described (Cai et al., Peptides 26:1481-5, (2005); Al-Obeidi t al., J. Am. Chem. Soc. 111:3413-3416 (1989); Kask et al., Endocrinology 139:5006-5014 (1998); Nijenhuis et al., Peptides 24:271-80, (2003); Schoth et al., Peptides 18:1009-13 (1997), Pat. Appl. No. WO06/073772; U.S. Pat. No. 6,716,810).
Alpha-MSH has potent anti-inflammatory effects mediated by centrally expressed melanocortin receptors. At the molecular level, alpha-MSH beneficially modulates various pathways implicated in regulation of inflammation and protection, such as NF-kB activation, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell and inflammatory cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of alpha-MSH have been validated in several inflammatory animal models ((for review see Brzoska et al., Endocr Rev. 29:581-602 (2008); Getting et al., Scientific World Journal. 9:1394-414 (2009), Maaser et al., Ann N Y Acad. Sci. 1072:123-34 (2006)).
In recent years, the pro-opiomelanocortin (POMC)-derived peptides (melanocortins, e.g. alpha-MSH, beta-MSH and gamma-MSH, and adrenocorticotrophic hormone (ACTH)) having in common the tetrapeptide sequence His-Phe-Arg-Trp have been implicated in a plethora of diseases such as sexual impotence, frigidity, anorexia, cachexia, haemorrhagic shock, myocardial infarction, ischemia, neuropathic pain, rheumathoid arthritis, inflammatory bowel disease, nerve injury and neuropathies, by acting via different melanocortin receptors (for review Bertolini et al., Pharmacol Res. 59:13-47 (2009); Brzoska et al., Endocrine Rev. 29:581-602 (2008)).
Thus, a need exists to develop additional melanocortin receptor binding conjugates to treat obesity and other melanocortin system-mediated conditions.